The present invention relates to a multi-step process for the preparation of 4,5-diamino shikimic acid derivatives, especially for the preparation of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester and its pharmaceutically acceptable addition salts starting from furan as well as new specific intermediates.
4,5-diamino shikimic acid derivatives, especially the (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester and its pharmaceutically acceptable addition salts are potent inhibitors of viral neuraminidase( J. C. Rohloff et al., J.Org.Chem., 1998, 63, 4545-4550; WO 98/07685).
A multi step synthesis of (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester from (xe2x88x92)-quinic acid or (xe2x88x92)-shikimic acid is described in (J. C. Rohloff et al, loc.cit.).
Both (xe2x88x92)-quinic acid and (xe2x88x92)-shikimic acid are starting compounds which are rather expensive and hardly accessible in technical quantities. A multi step synthesis capable to run on a technical scale should therefore preferably be based on starting compounds that are more attractive in price and available in technical quantities.
An object of the present invention therefore is to provide such a new access to the 4,5-diamino shikimic acid derivatives mentioned above in good yields and excellent quality.
It was found that the following synthesis could achieve this object.
The present invention therefore relates to a process for the preparation of a 4,5-diamino shikimic acid derivative of formula 
and pharmaceutically acceptable addition salts thereof
wherein
R1 is an optionally substituted alkyl group,
R2 is an alkyl group and
R3 and R4, independent of each other are H or an amino protecting group, with the proviso that not both R3 and R4 are H, a process
which is characterized by steps a) through g), wherein
step a)
furan is reacted with an acrylic acid derivative of the formula 
wherein R2 is as above to form a bicyclo compound of formula 
wherein R2 is as above,
step b)
the 2R-exo isomer of the bicyclo compound of formula (III) is separated,
step c)
this 2R-exo isomer of the bicyclo compound of formula (III) is reacted with an azide to form an aziridine of formula 
wherein R2 is as above and wherein R5 is the organic azide residue then,
step d)
eliminative ring opening is effected to yield a cyclohexene aziridine derivative of formula 
wherein R2 and R5 are as above,
step e)
a substituent R6 is introduced in the free OH-position and the aziridine ring is opened to give a cyclohexene derivative of formula 
wherein R1, R2 and R5 are as above and R6 is a OH-protecting group,
step f)
R5 is removed to yield a 4-amino cyclohexene derivative of formula 
wherein R1, R2 and R6 are as above
this 4-amino cyclohexene derivative of formula (VII) is finally processed to the 4,5-diamino shikimic acid derivatives of formula (I) by
step g)
comprising either g11 transformation of the 4-amino cyclohexene derivative of formula (VII) into an aziridine of formula 
wherein R1 and R2 are as above,
g12 formation of the azide of formula 
wherein R1, R2, R3 and R4 are as above and
g13 reduction and, if necessary the formation of the pharmaceuticallyacceptable addition salt, or
g21 transformation of the 4-amino cyclohexene derivative formula (VII)
into a 5-N-substituted-4,5-diamino shikimic acid derivative of formula 
wherein R1 and R2 are as above and R7 and R8, independent of each other are H or an amino protecting group, with the proviso that not both R7 and R8 are H
g22 acylation of the amino group in position 4 and
g23 releasing the amino group in position 5 and, if necessary the formation of the pharmaceutically acceptable addition salt.
The term alkyl in R1 has the meaning of a straight chained or branched alkyl group of 1 to 20 C-atoms, expediently of 1 to 12 C-atoms. Examples of such alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl, pentyl and its isomers, hexyl and its somers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its somers, undecyl and its isomers and dodecyl and its isomers.
This alkyl group can be substituted with one or more substituents as defined in e.g. WO 98/07685. Suitable substituents are alkyl of 1 to 20 C-atoms (as defined above), alkenyl with 2 to 20 C-atoms, cycloalkyl with 3 to 6 C-atoms, hydroxy, alkoxy with 1 to 20 C-atoms, alkoxycarbonyl with 1 to 20 C-atoms, F, Cl, Br, and I. Preferred meaning for R1 is 1-ethylpropyl.
R2 is a straight chained or branched alkyl group of 1 to 12 C-atoms, expediently of 1 to 6 C-atoms, as exemplified above.
Preferred meaning for R2 is ethyl.
The substituent R6 refers to any substituent for OH groups conventionally used and known in the art such as hydroxyl-protecting groups. They are described e.g. in xe2x80x9cCompendium of Organic Methodsxe2x80x9d or in xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, ed. March J., John Wiley and Sons, New York, 1992, 353-357.
Preferably R6 is a sulfonyl group, more preferably optionally substituted aryl sulfonyl or alkyl sulfonyl such as p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-bromo benzenesulfonyl, trifluoromethanesulfonyl or methanesulfonyl, most preferably methanesulfonyl.
The term amino protecting group in R3 and R4 or R7 and R8 refers to any substituent conventionally used and known in the art for protecting amino groups. They are described e.g. in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Theodora W. Greene et al., John Wiley andSons Inc., New York, 1991, 315-385. Suitable substituents are also given in e.g. the WO 98/07685.
Preferred substituents for R3 and R4 are alkanoyl groups, more preferably lower alkanoyl with 1 to 6 C-atoms such as hexanoyl, pentanoyl, butanoyl (butyryl), propanoyl (propionyl), ethanoyl (acetyl) and methanoyl (formyl). Preferred alkanoyl group and therefore preferred meaning for R3 is acetyl and for R4 is H.
Preferred substituent for R7 and R8 is straight chained or branched alkenyl with 2 to 6 C-atoms, preferably allyl or an analog thereof. Suitable analog of allyl is an allyl group which is substituted on the xcex1-, xcex2- or xcex3-carbon by one lower alkyl, lower alkenyl, lower alkynyl or aryl group. Suitable examples are e.g. 2-methylallyl, 3,3-dimethylallyl, 2-phenylallyl, or 3-methylallyl. Most preferred meaning for R7 is allyl and for R8 is H.
Preferred 4,5-diamino shikimic acid derivative of formula (I) is the (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester and the ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (1:1).
Step a)
Step a) comprises a Diels-Alder reaction of furan with an acrylic acid derivative. Diels-Alder reactions per se are known to the skilled in the art (see e.g. Tetrahedron Letters, 23, 1982, 5299-5302). The present conversion can therefore be performed following the methods and conditions described in the art.
Suitable derivatives of an acrylic acid are the esters and the amides, preferably the esters, more preferably lower alkyl esters of acrylic acid.
Usually this type of reaction needs the presence of Lewis acids. Suitable Lewis acids are magnesium halogenides such as magnesium chloride, magnesium bromide or magnesium iodide or zinc halogenides such as zinc chloride, zinc bromide or zinc iodide. Preferred Lewis acid was found to be zinc chloride.
As a rule catalytic amounts of the Lewis acid are applied, however it was surprisingly found that stoechiometric amounts or even an excess of the Lewis acid, preferably of zinc chloride within a reasonable time lead to an excellent exo/endo ratio of the bicyclo compound of formula (III) of up to 9:1.
Preferably stoichiometric amounts of zinc chloride are used.
Convenient solvent for step a) is the reactant acrylic acid derivative itself, used in an excess of up to 50%. It is however always possible to add an inert solvent.
The reaction temperature is not critical and can be chosen in the range of 20xc2x0 C. to 70xc2x0 C.
After termination of the reaction, recovery of the product can take place using methods well known to the skilled in the art.
Step b)
Step b) comprises separation of the 2R-exo isomer of the bicyclo compound of formula (III), preferably of the optical pure 2R-exo isomer of the bicyclo compound of formula (III).
Step a) provides the racemate of an exo/endo mixture of the bicyclo compound, wherein the exo form in the mixture is enriched up to a ratio of 9:1.
As a principle, separation of endo and exo forms of a compound can take place by taking advantage of the different physical properties of these forms such as different boiling points. Separation of each of the two optical isomers, however, has to take place either by classical racemate resolution techniques or by a stereoselective methods, e.g. by an enzymatic approach.
The desired 2R-exo form of the bicyclo compound can accordingly be isolated by physical separation of the exo and endo forms by any conventional technique which separates compounds according to their differing physical properties, e.g. by distillation, then separation of the 2R-exo and 2S-exo isomers by converting the exo-ester into the respective acid and finally by a subsequent racemate resolution using classical resolving agents such as (xe2x88x92)-ephedrin hydrochloride or S-(xe2x88x92)-1-phenyl ethylamine.
Preferably, however the exo/endo mixture of step a) is treated with an enzyme which is capable of specifically hydrolyzing the 2S-exo isomer and leaves the 2R-exo isomer unhydrolyzed. It was found that, ideally, lipases of the EC class 3.1.1.3 or lipoprotein lipases of the EC class 3.1.1.34 are used. Suitable representatives of these classes are lipases of the genus Candida, more preferably of Candida antarctica. Such lipases are commercially available. Most preferred enzyme is the B-form of lipase Candida antarctica which is offered under the tradename CHIRAZYME(copyright)L2 from Roche Diagnostics or as LIPASE SP-525 from Novo Nordisk.
As a common alternative immobilized enzymes may be used.
The reaction is usually carried out in an aqueous solution, preferably a monophasic or biphasic aqueous system, most preferably in a biphasic system with an apolar solvent as co-solvent. Suitable co-solvents are alkanes, cycloalkanes or cycloalkenes. Cyclohexane, cyclohexene and octane was found to be the most preferred co-solvent.
The common aqueous buffer solutions known to be used for biochemical conversions are used in order to maintain the pH in the range of 6.5 to 8.0. Suitably sodium or potassium phosphate buffers or borate buffers can be applied. Such a buffer solution can additionally contain NaCl or KCl in a concentration of 50 to 300 mM. A preferred buffering system could e.g. contain 0.1 M KCl and 5 mM potassium borate pH 7.5.
The ratio organic solvent/aqueous phase is in the range of 1:10 to 3:2. Overall substrate concentration is expediently chosen in the range of 5 to 20 wt. %, preferably in the range of 5 to 10 wt. %.
The reaction temperature is not critical. A suitable reaction temperature is 0xc2x0 C. to 25xc2x0 C., preferably close to freezing temperature of the reaction mixture.
The resulting 2S-exo acid is preferably neutralized by the controlled addition of a base such as NaOH or KOH, whereby the uncleaved 2R-exo ester together with the endo isomers remains in the organic phase and is separated by way of extraction with a common organic solvent.
Separation of the 2R-exo ester from the endo isomers can take place by a distillation in vacuo, preferably at a temperature in the range of 70xc2x0 C. and 100xc2x0 C. and a pressure of 0.1 mbar to 10 mbar.
Step c)
Step c) comprises the reaction of the 2R-exo isomer of the bicyclo compound of formula (III) with any azide, R5xe2x80x94N3, conventionally known or used in the art of organic synthesis. R5 is any organic azide residue conventionally known or used in the art of organic synthesis.
Particularly suitable azides are found to be these which are capable to form an aziridine ring in endo-position to the bridgehead of the bicyclic system. Unexpectedly phosphoryl azides of the formula
R5xe2x80x2N3xe2x80x83xe2x80x83XI
wherein R5 is dialkoxyphosphoryl or diaryloxyphosphoryl, preferably diaryloxyphosphoryl, most preferably diphenyloxyphosphoryl fulfilled this task.
Most preferred phosphoryl azide is the diphenyloxy-phosphoryl azide (DPPA).
The preference of DPPA is mainly based on its availability in technical quantities and its lower toxicity compared to the dialkoxyphosphoryl azides.
The phosphoryl azide is conveniently added in an amount of 0.8 equivalents to 1.0 equivalents relating to the 2R-exo bicyclo compound gained in step b). Preferably stoichiometric amounts of the phosphoryl azide are added.
The choice of a solvent is not critical as long as it is inert to the reactants. Toluene or dioxane were found to be suitable solvents.
The reaction temperature is not critical and can be chosen expediently between 40xc2x0 C. and 80xc2x0 C.
In case R5 has the preferred meaning of diaryloxy phosphoryl, a transesterification can be performed to transform the diaryloxy phosphoryl group into a dialkoxy phosphoryl group.
Accordingly the organic azide residue R5 is dialkoxy-phosphoryl, preferably di-(C1-6) alkoxy-phosphoryl, most preferably diethoxy-phosphoryl. Transesterifications are methods known to the skilled in the art, but as a rule take place in the presence of an alcoholate in the corresponding alcohol. Within the most preferred method transesterification takes place in the presence of sodium ethanolate in ethanol.
Step d)
Step d) comprises eliminative ring opening of the aziridine of formula (IV) to the cyclohexene aziridine derivative of formula (V).
This reaction is performed in the presence of a strong organic base. Expediently alkali-bis -(trialkylsilyl) amides, preferably alkali-bis-(trimethylsilyl) amides such as lithium bis-(trimethylsilyl) amide, sodium-bis-(trimethylsilyl) amide or potassium-bis-(trimethylsilyl) amide are used.
Usually the strong organic base is used in amount of 1.0 equivalent to 2.5 equivalents relating to one equivalent of the aziridine of formula (IV).
The choice of a solvent also for this step is not critical as long as it is inert to the reactants. Dioxane or tetrahydrofuran were found to be suitable solvents.
The reaction temperature is also not critical and may expediently be maintained in the range of xe2x88x9280xc2x0 C. to 0xc2x0 C., preferably in the range of xe2x88x9280xc2x0 C. to xe2x88x9220xc2x0 C.
The cyclohexene aziridine of formula (V) can be isolated after an acidic work up applying methods known to the skilled in the art.
Step e)
Step e) comprises introduction of a substituent R1 in the free OH-position and ring opening of the aziridine ring to give cyclohexene derivatives of formula (VI).
The sequence of the reactions introducing substituent R6 into the free OH-position and opening the ring is not critical. Preferably, substituent R6 is introduced into the free OH-position first, followed by ring opening.
Compounds and methods for effecting such a substitution are well known in the art and described e.g. in xe2x80x9cCompendium of Organic Methodsxe2x80x9d or in xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, ed. March J., John Wiley and Sons, New York, 1992, 353-357.
It was found that the hydroxy group is preferably transformed into a sulfonic acid ester, R6 therefore preferably is a sulfonyl group, more preferably optionally substituted aryl sulfonyl or alkyl sulfonyl such as p-toluenesulfonyl, p-nitrobenzenesulfonyl, p-bromo benzenesulfonyl, trifluoromethanesulfonyl or methanesulfonyl, most preferably methanesulfonyl.
Agents commonly used for producing sulfonic acid esters e.g. are the halogenides or the anhydrides of the following sulfonic acids: methanesulfonic acid, p-toluenesulfonic acid a p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid or trifluoromethanesulfonic acid.
Preferred agent is a halogenide or anhydride of methanesulfonic acid such as methane sulfonylchloride.
The sulfonylating agent is expediently added in an amount of 1.0 to 1.2 equivalents relating to one equivalent of the cyclohexene aziridine of formula (V).
Although none of these variables are critical, usually the reaction takes place in an inert solvent such as in ethylacetate, at a reaction temperature of 0xc2x0 C. to 20xc2x0 C. and in the precence of an organic base.
For effecting the ring opening of the aziridine ring further the 0-substituted cyclohexane derivative of formula (V) is converted with an alcohol R1OH, wherein R1 is as above, in the presence of a Lewis acid. Following the preferences of R1 given above most suitable alcohol is pentane-3-ol.
A suitable Lewis acid is e.g. bortrifluoride ethyl etherate which is usually added in an amount of 1.0 equivalent to 1.5 equivalents relating to one equivalent of the cyclohexene aziridine of formula (V).
Although none of these reactions are critical, the reaction expediently takes place in an inert solvent such as in a halogenated hydrocarbon like methylene chloride at temperatures between 0xc2x0 C. and 40xc2x0 C.
Alternatively the reaction can be performed without extra solvent thereby using the respective alcohol in sufficient excess.
Step f)
Step f) covers the removal of R5 to yield the 4-amino cyclohexene derivative of formula (VII).
R5 as outlined above preferably being dialkyl phosphoryl is advantageously splitted off using strong acidic conditions. Suitably a strong mineral acid such as sulfuric acid can be used. In order to achieve better crystallization the sulfate formed can be transformed with hydrochloric acid into the hydro chloride.
Although it is not critical to the reaction, the reaction conveniently takes place in a polar organic solvent such as in alcohols, preferably in alcohols which correspond to the ester residue R2.
Step g)
As shown above step g) offers two different ways to come to the 4,5-diamino shikimic cid derivative of formula (I).
One way comprising the steps g11 to g13 passes an azide intermediate, whereby the other way comprising steps g21 to g23 follows an azide free route. Preferred route is the azide free route g21 to g23.
Steps g11 to g13.
Step g11)
The transformation of the 4-amino cyclohexene derivative of formula (VII) to the aziridine of formula (VIII) can happen by reaction with a tertiary amine in the presence of an inert solvent.
Preferably triethylamine is selected as tertiary amine.
The tertiary amine is preferably applied in amounts of 2.0 equivalents to 2.5 equivalents relating to one equivalent of 4-amino cyclohexene derivative of formula (VII).
The choice of solvents is not critical. Good results have been achieved with ethylacetate or tetrahydrofuran.
Although not critical to the reaction, the reaction usually takes place at a temperature of 40xc2x0 C. to 80xc2x0 C.
steps g12, g13 
These steps comprise the conversion of the aziridine of formula (VIII) to an azide and the subsequent reduction to the end product. These steps are known in the art and can be processed following the disclosure in scheme 5 of J. C. Rohloff et al., J.Org.Chem., 1998, 63, 4545-4550 and the corresponding experimental part thereof, which is incorporated herein by reference. Preferably, the aziridine ring of the compound of formula (VIII) is opened by reaction with an azide to form an azidoamine, followed by acylation of the amino group of the azidoamine with at least one amino-protecting group to form the azide of formula (IX). The azide of formula (IX) is then reduced to form the 4,5-diamino shikimic acid of formula (I).
Steps g21 to g23 
step g21)
Step g21) comprises the transformation of the 4-amino cyclohexene derivative of formula (VII) into a 5-N-substituted-4,5-diamino shikimic acid derivative of formula (X).
This transformation is expediently effected with an amine of formula R7NHR8, wherein R7 and R8 have the meaning as stated above. Preferred amines are allylamine, diallylamine or 2-methylallylamine whereby allylamine is the most preferred.
In order to release the amine the salt of the 4-amino cyclohexene derivative of formula (VII) as obtained in step f) is expediently neutralized first, either by addition of a common inorganic base such as sodium bicarbonate or by using the amine formula R7NHR8 in excess.
The reaction with the amine itself can be performed in an inert solvent, applying either normal or elevated pressure at temperatures of 20xc2x0 C. to 150xc2x0 C. As a suitable solvent tert.-butyl methyl ether can be selected.
Step g22)
Step g22) comprises the acylation of the free amino function of the 5-N-substituted 4,5-diamino shikimic acid derivative of formula (X).
Acylation can be effected under strong acidic conditions by using acylating agents known to the skilled in the art. Acylating agent can be an aliphatic or aromatic carboxylic acid, or an activated derivative thereof, such as an acyl halide, a carboxylic acid ester or a carboxylic acid anhydride. Suitable acylating agent preferably is an acetylating agent such as acetylchloride, trifluoracteylchloride or acetic anhydride. Suitable aromatic acylating agent is benzoylchloride. Strong acids suitably used e.g. are mixtures of methanesulfonic acid and acetic acid or sulfuric acid and acetic acid.
Acylation however can also take place under non acidic conditions using e.g. N-acetyl-imidazole or N-acetyl-N-methoxy-acetamide.
Preferably, however, the acylation takes place under acidic conditions using 0.5 to 2.0 equivalents of acetic anhydride, 0 to 15.0 equivalents of acetic acid and 0 to 2.0 equivalents of methanesulfonic acid in ethyl acetate.
An inert solvent such as tert.-butyl methyl ether maybe added, it is however also possible to run the reaction without addition of any solvent.
Although not critical to the reaction, the temperature is preferably chosen in the range of xe2x88x9220xc2x0 C. to 100xc2x0 C.
Step g23)
Step g23) comprises release of the amino group in position 5 and, if desired, further transformation of the resulting 4,5-diamino shikimic acid derivative of formula (I) into a pharmaceutically acceptable addition salt.
Release of the amino group is expediently effected by isomerization/hydrolysis in the presence of a suitable metal catalyst. Expediently a precious metal catalyst such as Pt, Pd or Rh either applied on an inert support such as charcoal or alumina, or in complexed form can be used. Preferred catalyst is 5 to 10% palladium on carbon (Pd/C).
The catalyst is suitably used in an amount of 2 to 30 wt. %, preferably, 5 to 20 wt. % relating to the 5-N-substituted 4,5-diamino shikimic acid derivative of formula (X).
The isomerization/hydrolysis is advantageously carried out in an aqueous solvent. The solvent itself can be protic or aprotic. Suitable protic solvents are e.g. alcohols such as methanol, ethanol or isopropanol. Suitable aprotic solvent is e.g. acetonitrile or dioxane.
The reaction temperature is not critical, but is preferably chosen in the range of 20xc2x0 C. to 150xc2x0 C.
It was found that isomerization/hydrolysis is preferably effected in the presence of a primary amine.
Primary amines suitably used are ethylenediamine or ethanolamine, or suitable derivatives thereof. A particularly preferred primary amine is ethanolamine.
The primary amine is suitably used in an amount of 1.0 to 1.25 equivalents, preferably of 1.05 to 1.15 equivalents relating to the 5-N-substituted 4,5-diamino shikimic acid derivative of formula (X).
In order to completely hydrolyze any imines that may have formed in this step, the reaction mixture is preferably treated with a mineral acid e.g. with sulfuric acid or hydrochloric acid.
Though the 4,5-diamino shikimic acid derivative can be isolated e.g. by evaporation and crystallization, it is preferably kept in e.g. an ethanolic solution and then further transformed into the pharmaceutically acceptable addition salt following the methods described in J. C. Rohloff et al., J.Org.Chem., 1998, 63; 4545-4550; WO 98/07685).
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
The salt formation is effected in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methansulfonates, p-toluenesulfonates and the like are examples of such salts.
Preferred pharmaceutically acceptable acid addition salt is the 1:1 salt with phosphoric acid which can be formed preferably in ethanolic solution at a temperature of 50xc2x0 C. to xe2x88x9220xc2x0 C.
The invention further comprises a process for the preparation of the 2R-exo isomer of the bicyclo compound of formula 
This process is characterized by the treatment of the exo/endo mixture of the bicyclo compound of formula (III) as obtained from step a) with a lipase of the EC class 3. 1. 1. 3 or a lipoprotein lipase of the EC class 3. 1. 1. 34, the lipases thereby specifically hydrolyse the 2S-exo isomer and leaving the 2R-exo isomer untouched.
This specific process embodiment is identical to step b).
The respective description is incorporated herein by reference.
Accordingly, as stated under step b), preferred lipases are of the genus Candida antarctica. 
The invention further comprises a process for the preparation of an aziridine of formula 
wherein R2 is as above and wherein R5 is the organic azide residue.
This process is characterized by the conversion of a 2R-exo isomer of the bicyclo compound of formula 
wherein R2 is as above, with an azide.
This conversion is identical to step c) of the multistep synthesis described herein above. The respective description of step c) is incorporated herein by reference.
Preferred azide as stated above is diphenyloxy-phosphoryl azide (DPPA).
The following key intermediates are new and not known to the state of the art they accordingly are an essential element of the present invention. 
wherein R2 is as above and wherein R5 is the organic azide residue, preferably (1S,2S,4R,5R,6R)-3-(diethoxy-phosphoryl)-8-oxa-3-aza-tricyclo [3.2.1.0 2,4]octane-exo-6-carboxylic acid ethyl ester (with R2=ethyl and R5=diethoxy-phosphoryl) and (1S,2S,4R,5R,6R)-3-(diphenyloxy-phosphoryl)-8-oxa-3-aza-tricyclo [3.2.1.0 2,4]octane-exo-6-carboxylic acid ethyl ester (with R2=ethyl and R5=diethoxy-phosphoryl). 
wherein R2 and R5 are as above, preferably (1S,5S,6S)-7-(diethoxyphosphoryl)-5-hydroxy-7-aza-bicyclo [4.1.0]hept-2-ene-3-carboxylic acid ethyl ester (with R2=ethyl and R1=diethoxy-phosphoryl). 
wherein R1, R2, R5 and R6 are as above and its pharmaceutically acceptable salts, preferably (3R,4S,5S)-4-(diethoxyphosphorylamino)-3-(1-ethyl-propoxy)-5-methanesulfonyloxy-cyclohex-1-ene carboxylic acid ethyl ester (with R1=1-ethylpropyl, R2=ethyl, R5=diethoxy-phosphoryl and R6=methanesulfonyl). 
wherein R1, R2, R6 are as above and its pharmaceutically acceptable salts, preferably (3R,4S,5S)-4-amino-3-(1-ethyl-propoxy)-5-methanesulfonyloxy-cyclohex-1-ene carboxylic acid ethyl ester hydrochloride (with R1=1-ethylpropyl, R2=ethyl, R6=methanesulfonyl).